Squamous cell carcinoma of the oral cavity (SCCOC) is the sixth leading cause of cancer deaths worldwide. However, little is known about the cellular and molecular mechanisms of SCCOC tumor progression. In the prior funding period, we demonstrated that acquisition of anoikis-resistance is an important hallmark of oral epithelial tumor progression. Results of our cDNA microarray expression analysis of anoikis-resistant and - sensitive cells revealed that the S100A7 protein, a low-molecular-weight (11.4 kDa) Ca2+binding protein that belongs to S100 multigenic protein family, is differentially expressed in anoikis-sensitive and -resistant cells. Further analyses indicated that S100A7 is overexpressed in pre-invasive, well-differentiated SCCOC. However, with the progression to invasive carcinomas, S100A7 expression is often down-regulated or diminished in the late stages of tumorigenesis. While it is evident that S100A7 protein is critical to the tumorigenesis of certain cancers, it remains unclear whether S100A7 plays an oncogenic or tumor suppressive role in SCCOC given its biphasic expression. Our preliminary results show that despite its overexpression in premalignant oral lesions, S100A7 plays an important inhibitory role in SCCOC progression by down-regulating tumor growth, EMT, tumor invasion/metastasis at least in part through its role as a novel regulator of 2-catenin degradation. Thus, the central hypothesis of this application is that S100A7 plays an important role as a tumor suppressor in SCCOC development and progression, through its inhibition of cell proliferation, motility, EMT, and invasion by inhibition of 2-catenin, Twist, and Snail. This hypothesis will be tested in 4 specific aims, and it is our expectation that completion of the approaches outlined in these 4 aims will help us to define S100A7's role as a tumor suppressor in SCCOC and that this information will enhance our ability to clinically stage SCCOC and identify potential new targets for therapy.